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J. Biol. Chem., Vol. 282, Issue 15, 10841-10845, April 13, 2007

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Extension of Human Cell Lifespan by Nicotinamide Phosphoribosyltransferase^*

From the Robarts Research Institute and London Health Sciences Centre, Departments of Medicine (Cardiology), Biochemistry, Medical Biophysics, and Biology, University of Western Ontario, London, Ontario Canada N6A 5K8

Extending the productive lifespan of human cells could have major implications for diseases of aging, such as atherosclerosis. We identified a relationship between aging of human vascular smooth muscle cells (SMCs) and nicotinamide phosphoribosyltransferase (Nampt/PBEF/Visfatin), the rate-limiting enzyme for NAD⁺ salvage from nicotinamide. Replicative senescence of SMCs was preceded by a marked decline in the expression and activity of Nampt. Furthermore, reducing Nampt activity with the antagonist FK866 induced premature senescence in SMCs, assessed by serial quantification of the proportion of cells with senescence-associated -galactosidase activity. In contrast, introducing the Nampt gene into aging human SMCs delayed senescence and substantially lengthened cell lifespan, together with enhanced resistance to oxidative stress. Nampt-mediated SMC lifespan extension was associated with increased activity of the NAD⁺-dependent longevity enzyme SIRT1 and was abrogated in Nampt-overexpressing cells transduced with a dominant-negative form of SIRT1 (H363Y). Nampt overexpression also reduced the fraction of p53 that was acetylated on lysine 382, a target of SIRT1, suppressed an age-related increase in p53 expression, and increased the rate of p53 degradation. Moreover, add-back of p53 with recombinant adenovirus blocked the anti-aging effects of Nampt. These data indicate that Nampt is a longevity protein that can add stress-resistant life to human SMCs by optimizing SIRT1-mediated p53 degradation.

Received for publication, January 24, 2007 , and in revised form, February 15, 2007.

^* This work was supported by grants from the Heart and Stroke Foundation of Ontario (Grants HSFO T4458 and PRG 4854), the Canadian Institutes of Health Research (Grants PPP-73347 and MT11715), and the Krembil Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental movies showing time-lapse delineation of the changes discussed in the legend for Fig. 4.

¹ A recipient of a Heart and Stroke Foundation of Canada studentship.

² A recipient of a Heart and Stroke Foundation of Ontario Career Investigator Award. To whom correspondence should be addressed: London Health Sciences Centre, 339 Windermere Rd., London, Ontario N6A 5A5. Tel.: 519-663-3973; Fax: 519-434-3278; E-mail: gpickering{at}robarts.ca.

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